S. M. Mccann

Peptidergic and dopaminergic control of prolactin release

The control of prolactin release by the pituitary gland is complex. Hypothalamic control is predominantly inhibitory in nature and is mediated not only by dopamine, γ -aminobutyric acid (GABA) and possibly acetylcholine (ACh), but probably also by a peptidic prolactin-inhibiting factor (PIF). However, there is also stimulatory hypothalamic control of lesser significance which may be mediated by a variety of peptides acting singly or in concert. These would include thyrotropin-releasing hormone (TRH), oxytocin, vasoactive intestinal polypeptide (VIP), angiotensin, and possibly others. It is apparent that the lactotroph is responsive to stimulation and inhibition by a variety of peptides and small molecular weight transmitters. The release of these various agents is controlled by a host of small molecular weight and peptidic transmitters acting within the hypothalamus. There is evidence for inhibitory effects of dopamine and adrenaline, stimulatory effects of noradrenaline, inhibitory or stimulatory effects of GABA, and stimulatory effects of a variety of peptides and inhibitory effects of others. Of these, the stimulatory influence of the opioid peptides is best established. Additionally, hypothalamic alterations of prolactin-releasing factor (PRF) and PIF release may be brought about by prostacyclin. Prolactin has an important short-loop feedback action to inhibit its own release, possibly via a dopaminergic mechanism. The incidence of hyperprolactinemia, frequently brought about by prolactinomas, is relatively high. When caused by prolactinomas, hyperprolactinemia can be corrected by microsurgery. Plasma prolactin can be lowered and the tumors reduced in size with the dopamine agonist α -bromoergocryptine.

The Role of Brain Peptides in Neuroimmunomodulation

Since neuroimmunomodulation is brought about in part, at least, by secretion of pituitary hormones involved in stress and immune responses, we review briefly the hypothalamic control of the release of ACTH, growth hormone, and prolactin. The release of ACTH is controlled particularly by corticotropin-releasing factor (CRF), but vasopressin has intrinsic releasing activity and potentiates the action of CRF at both hypothalamic and pituitary levels. Oxytocin may even potentiate the action of CRF, but has little, if any, ACTH-releasing activity by itself. In addition, epinephrine may augment responses to the CRFs. In contrast, growth hormone is under dual control by growth-hormone-releasing factor (GRF) and somatostatin, and prolactin is under multifactorial control by a series of inhibitors and stimulators. Dopamine is accepted as a physiological prolactin-inhibiting factor (PIF), but probably GABA and possibly acetylcholine as well are PIFs. There is good evidence for a peptide PIF as well. There are a number of prolactin-releasing factors (PRFs) which include oxytocin, vasoactive intestinal polypeptide, PHI and TRH. Several other peptides can also release prolactin, including angiotensin II. In response to stress there is a complex interaction of peptides intrahypothalamically. CRF augments its own release by an ultra short-loop positive feedback, and there is negative ultra short-loop feedback of GRF and somatostatin. Vasopressin appears to augment CRF release as well as to act directly on the pituitary, and there are complex interactions of various peptides to influence prolactin and GH release.

The Involvement of Cyclic-3',5'-AMP in the Release of Hormones from The Anterior Pituitary in Vitro

Summary DBcAMP significantly increased the release of GH but not of LH, FSH, TSH, or PRL, except in the presence of hypothalamic extract when it augmented the release of LH, FSH, and GH, reversed the inhibition of PRL, but did not further influence TSH release. Theophylline increased release of GH and PRL while inducing increased tissue content of cAMP without consistently increasing the release of TSH, LH, or FSH. Hypothalamic extractor K+-stimulated hormone release was consistently and significantly potentiated by theophylline. Neither hypothalamic extract, increased [K+], nor synthetic TRH and LRH were able to raise tissue content of cAMP while producing their expected effects on hormone release. Cholera enterotoxin produced a highly significant increase in tissue content of the cyclic nucleotide but increased the release of GH only, and not that of LH, FSH, TSH, or PRL. DBcAMP was able to lower the threshold concentration of K+ required to stimulate release of GH, LH, and FSH and also to augment K+-stimulated release to the higher levels induced by the hypothalamic releasing hormones. It did not augment K+-induced release of TSH.

Purification of FSH-releasing factor : its dissimilarity from LHRH of mammalian, avian, and piscian origin

Sheep stalk median eminence fragments were lyophylized, extracted and filtered through a column of Sephadex G-25. The fractions were then assayed for the presence of LHRH by radioimmunoassay (RIA) and bioassayed for FSH and LH-releasing activity following their IV injection into ovariectomized, estrogen progesterone-blocked rats. The radioimmunoassayable LHRH emerged from the column at the same position from which it emerged many years before when LH was measured by bioassay. This same region also contained the LH-releasing activity as measured by bioassay. FSH-releasing activity was present in two tubes just preceding the emergence of the bio- and immunoassayable LHRH. The activity was highly significant and there was no LH-releasing activity in the fractions. They contained much less LHRH as determined by RIA than is sufficient to evoke LH release in this assay. The FSH-releasing activity was recovered in the same fractions in which it was found many years ago with this same assay but with measurement of plasma FSH by bio-rather than immunoassay as employed here. A dose-related release of LH was obtained by injection of LHRH in this assay but there was no significant FSH release even with a dose of 27 ng of LHRH per rat. To determine if one of the LHRHs of lower forms might be FSH-RF, Chicken I and II LHRH and Salmon LHRH were also assayed for FSH- and LH-releasing activity. Each of these peptide possessed LH-releasing activity, albeit much less than that of the mammalian peptide but had no FSH-releasing activity whatsoever.(ABSTRACT TRUNCATED AT 250 WORDS)

The effect of intraventricular gamma aminobutyric acid (GABA) on hypothalamic catecholamines and LHRH and on pituitary hormone release

Abstract The present experiments were designed to evaluate the role of catecholamines in mediating the actions of GABA on pituitary hormone release following its intraventricular injection. GABA was administered intraventricularly, at doses of 0.1 and 4 μMol, to chronically ovariectomized rats. Five and 15 min after intraventricular injection, the animals were sacrificed by decapitation. Blood was collected for LH and PRL determination by RIA, and brains were frozen for subsequent determination of LHRH by RIA, and dopamine (DA) and norepinephrine (NE) by radioenzymatic assay. Brain areas analyzed included the median eminence (ME), medial basal hypothalamus (MBH) and suprachiasmatic-medial preoptic area (Sch-PO). Controls received an equal volume (2 μl) of saline. As previously observed, GABA had opposite effects on prolactin (PRL) release depending on the dose employed. A decline in serum PRL was induced by a low (0.1 μMol) dose, whereas a larger (4 μMol) dose induced an increase in PRL levels. LH levels were increased only with the 4 μMol dose. The elevated LH values were paralleled by an increase in LHRH levels in the Sch-PO region 15 min after GABA. Marked changes in catecholamines, particularly in DA, were seen after GABA injection. Significant increments in DA levels in the ME were seen 5 and 15 min after the 0.1 μMol dose of GABA. Similarly, this low dose of GABA induced a marked increase in DA levels in the anterior-pituitary (AP) gland at 15 min. No changes in DA were seen in either MBH or Sch-PO areas. The 4 μMol dose of GABA induced only a small increase in AP levels of DA, without altering the amine levels in any of the brain areas examined. NE levels in the ME were elevated 5 min after the administration of either dose of GABA. No changes in NE were seen in either the MBH or Sch-PO areas. These results indicate that intraventricular GABA injection not only alters pituitary hormone release but also release of DA and NE from terminals in the ME. The released catecholamines may be important in mediating the effects of GABA on releasing factor discharge. In addition, the DA released may have acted directly on the AP to inhibit release of PRL.

Hypothalamic Areas Involved in Prostaglandin(PG)-Induced Gonadotropin Release. I: Effects of PGE2 and PGF2α Implants on Luteinizing Hormone Release1

Ovariectomized rats had a cannula inserted unilaterally within various hypothalamic areas. Several days later they were primed with a sc dose of 10 microng of estradiol benzoate (Eb). Two days after priming they were etherized and an initial blood sample was drawn from the external jugular vein. An inner cannula containing PGE2 or PGF2alpha at its tip was inserted into the previously implanted outer cannula. Blood samples were drawn at 20, 40, 60, and 120 min following the implantation. PGE2 induced a 4-5-fold increase in plasma LH 40 to 60 min following its implantation in the arcuate nucleus-median eminence region (ARH-ME). Levels were already significantly elevated at 20 min. When PGE2 was placed slightly more dorsally, close to the ventromedial nucleus (VMH), LH titers rose to comparable levels but only after a delay of 120 min. PGE2 implanted in the caudal portion of the ARH-ME or dorsally in the VMH-dorsomedial nuclei, barely increased plasma LH, whereas its placement in the anterior portion of the ARH-ME clearly elevated LH titers. PGE2 implants located more than 1 mm lateral from the midline or outside the hypothalamus were ineffective. When PGE2 was placed in the preoptic area (POA) or anterior ventral portion of the anterior hypothalamic area (AHA), plasma LH levels rose strikingly, the first significant increase being observed at 20 min. PGE2 implants located in the vicinity of the paraventricular nucleus-dorsal portion of AHA were much less effective. PGF2alpha implanted in the ARH-ME or POA induced a small increase in plasma LH and the implantation of empty cannulae in the same areas was ineffective. Intrapituitary implants of PGE2 failed to alter plasma LH significantly. The results indicate that PGE2 acts at the ARH-ME region to induce LH release and that an even more effective site of action seems to be located in the POA-AHA. Since these are areas which contain LHRH, the results support the view that PGs can activated LHRH-secreting neurons in these regions.

Role of central nervous system neurotransmitters in mediating the effects of morphine on growth hormone-and prolactin-secretion in the rat

Unanesthetized adult male rats with indwelling right atrial cannulae were used in the majority of experiments. Morphine (MOR, 3.0 mg/kg) caused a large but transient increase in both GH and PRL levels, which could be prevented with naloxone. Disruption of central noradrenergic function with diethyldithiocarbamate (400 mg/kg) or phenoxybenzamine (15 mg/kg) abolished the GH-releasing effect of MOR, without interfering with the PRL secretory response. Depletion of brain serotonin stores with p-chlorophenylalanine (300 mg/kg) or 5,7-dihydroxytryptamine or administration of serotonin receptor blocker, cyproheptadine (2.5 mg/kg), did not diminish the GH respnse to MOR but it inhibited, or in the case of 5,7-DHT treatment abolished the activation of PRL secretion. Additionally, metergoline (0.1 and 1.0 mg/kg), another serotonin receptor blocker, caused an inhibition of the GH-releasing action of MOR; however, this inhibition was reversed by pretreatment with spiroperidol (0.1 mg/kg). Metergoline also markedly diminished the MOR-induced elevation of PRL. Inhibition of catecholamine synthesis with alpha-methyl-p-tyrosine (alpha-MT, 250 mg/kg) blunted the effect of MOR on GH; however, dopamine receptor blockers, spiroperidol (0.01 and 0.1 mg/kg) or (+)butaclamol (0.3 and 1.3 mg/kg), were without any influence. alpha-MT or spiroperidol did not alter the effect of MOR on PRL secretion, but the higher dose of (+)butaclamol suppressed it. It is concluded that the GH-releasing action of MOR requires unimpaired functioning of the central noradrenergic system, while the serotonergic and dopaminergic systems appear to play no significant role in it. In contrast, serotonergic systems seem to be essential for the activation of PRL secretion, whereas the noradrenergic system is not involved. It remains uncertain whether morphine activtes PRL secretion also through inhibition of dopaminergic activity. We favor the view that the dopaminergic component participates in the PRL activation by MOR, but that its contribution to the overall effect is rather small.

Evidence for Hormonal Participation in the Natriuretic and Kaliuretic Responses to Intraventricular Hypertonic Saline and Norepinephrine

Summary To examine if hypothalamic or pituitary hormones are involved in the induction of the natriuresis which follows the injection of hypertonic saline or norepi-nephrine into the third ventricle, lesions were placed in the median eminence and the responses to intraventricular norepineph-rine or hypertonic saline were evaluated. Sham lesions in which the electrode was lowered into the brain but stopped short of the hypothalamic region did not interfere with the natriuresis, kaliuresis, and antidi-uresis induced by the third ventricular injection of either hypertonic sodium chloride or norepinephrine. Lesions in the median eminence which induced diabetes insipidus as evidenced by an increase in water consumption to approximately four times normal completely abolished the natriuresis and kaliuresis in response to intraventricular hypertonic saline or norepinephrine and diminished the antidiuresis. The observations suggest the possibility that a natriuretic hor-mone(s) is involved in the induction of central natriuresis.

Lesions of the sexually dimorphic nucleus of the preoptic area: Effects upon LH, FSH and prolactin in rats

Bilateral lesions were placed in the sexually dimorphic nucleus of the preoptic area (SDN-POA) in castrated adult male rats in an attempt to determine a physiologic role for this nucleus. These lesions significantly attenuated the increase in plasma FSH and LH due to simultaneous castration at 24 hr, and at 7 and 14 days following surgery, and significantly decreased the levels of plasma prolactin on comparison with pre-operative values and those of castrated controls. When rats were castrated and lesions placed at 14 days following castration, plasma levels of FSH, LH and prolactin were significantly decreased at 24 hr and at 7 days following surgery. Lesions which were placed lateral or caudal to the SDN-POA simulated the effects of lesions placed within the SDN-POA upon plasma LH, FSH and prolactin, with lateral lesions being most effective. However, lesions which were placed dorsal or rostral to the SDN-POA had no effect. The results of these studies suggest that the SDN-POA may be involved in the regulation of LH, FSH, and prolactin release.

The Effects of Interruption of the Ventral Noradrenergic Pathway on the Proestrous Discharge of Prolactin in the Rat

Summary 6-Hydroxydopamine was mi-croinjected bilaterally into the ventral nor-adrenergic tract at the level of the interpe-duncular nucleus. Effective injections into the tract as indicated by the lesions induced and by a decline in the catecholamine fluo-resence in the anterior hypothalamus were associated with a complete blockade of the rise in prolactin which occurs on the afternoon of proestrus and, in fact, a decline in prolactin ensued. Lesions which were asymmetrical or missed the ventral noradrenergic tract had only a slight effect in inhibiting the release of prolactin on the afternoon of proestrus. All lesions were capable of blocking the release of LH on the afternoon of proestrus. It is postulated that increased impulse traffic along the ventral noradrenergic tract induces the proestrous discharge of prolactin and LH or that, alternatively, tonic activity in this tract is required for this release to occur.